title: A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice.
abstract: Canavan's disease (CD) is a fatal pediatric leukodystrophy caused by mutations in aspartoacylase (AspA) gene. Currently, there is no effective treatment for CD; however, gene therapy is an attractive approach to ameliorate the disease. Here, we studied progressive neuropathology and gene therapy in short-lived (≤ 1 month) AspA(-/-) mice, a bona-fide animal model for the severest form of CD. Single intravenous (IV) injections of several primate-derived recombinant adeno-associated viruses (rAAVs) as late as postnatal day 20 (P20) completely rescued their early lethality and alleviated the major disease symptoms, extending survival in P0-injected rAAV9 and rAAVrh8 groups to as long as 2 years thus far. We successfully used microRNA (miRNA)-mediated post-transcriptional detargeting for the first time to restrict therapeutic rAAV expression in the central nervous system (CNS) and minimize potentially deleterious effects of transgene overexpression in peripheral tissues. rAAV treatment globally improved CNS myelination, although some abnormalities persisted in the content and distribution of myelin-specific and -enriched lipids. We demonstrate that systemically delivered and CNS-restricted rAAVs can serve as efficacious and sustained gene therapeutics in a model of a severe neurodegenerative disorder even when administered as late as P20.
authors.affiliation: 1] Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA [2] Department of Microbiology & Physiological Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Seemin Seher
authors.initials: SS
authors.lastname: Ahmed
authors.forename: Huapeng
authors.initials: H
authors.lastname: Li
authors.forename: Chunyan
authors.initials: C
authors.lastname: Cao
authors.forename: Elif M
authors.initials: EM
authors.lastname: Sikoglu
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Denninger
authors.forename: Qin
authors.initials: Q
authors.lastname: Su
authors.forename: Samuel
authors.initials: S
authors.lastname: Eaton
authors.forename: Ana A
authors.initials: AA
authors.lastname: Liso Navarro
authors.forename: Jun
authors.initials: J
authors.lastname: Xie
authors.forename: Sylvia
authors.initials: S
authors.lastname: Szucs
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.forename: Constance
authors.initials: C
authors.lastname: Moore
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Kirschner
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: Reuben
authors.initials: R
authors.lastname: Matalon
authors.forename: Guangping
authors.initials: G
authors.lastname: Gao
mesh_terms: D000581:Amidohydrolases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017825:Canavan Disease / Q000473:pathology / Q000628:therapy*; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009928:Organ Specificity; D014961:X-Ray Diffraction
chemical_list: D035683:MicroRNAs; D000581:Amidohydrolases; C019751:aspartoacylase